Introduction
Peripheral arterial disease (PAD) is a common cardiovascular disease that significantly increases cardiovascular (CV) and overall mortality and morbidity. Unfortunately, in comparison with patients with coronary heart disease, PAD patients are often unrecognised and not optimally treated.
In patients with PAD, the importance of a holistic multidisciplinary approach, which includes diagnosis, treatment, monitoring and prevention, is emphasised. The initial steps are screening the patients at high risk and optimal pharmacological treatment introduction with the aim of preventing and reducing major adverse cardiovascular events (MACE) and major adverse limb events (MALE), improving patient survival, reducing the risk of hospitalisation, reducing the need for endovascular and/or surgical intervention, and improving the patients’ quality of life. (1)
More commonly, peripheral arterial disease is considered the disease of peripheral arteries of lower limbs (Figure 1). Risk factors for PAD are the same as for other atherosclerotic vascular territories and include non-modifiable risk factors such as age, sex and family history and modifiable risk factors such as smoking, diabetes, dyslipidemia and arterial hypertension. In patients with abdominal aortic aneurysm (AAA), the most significant risk factors are male gender and smoking. LDL cholesterol is the leading factor in the development of atherosclerosis, along with diabetes, arterial hypertension and smoking, and each of these increases the risk of developing PAD two to four times.
Approach to patients with peripheral arterial disease
In the initial approach to PAD patients, the first step is a clinical examination and laboratory analysis of CV risk factors. The clinical examination includes a family CV history, patient’s history and symptoms, while the physical examination includes palpation of peripheral pulses, auscultation of the femoral, carotid and abdominal territories, auscultation of the heart, and an examination of the legs. As part of the laboratory workup, it is important to determine the complete blood count, C-reactive protein (CRP), cholesterol levels (including Lp(a)), fasting glycemia and HbA1c, renal and liver function, electrolytes and coagulation parameters.
PAD patients have a reduced walk distance, which leads to the impairment of the functional status, and thus the quality of life. The gold standard for evaluating a walk distance is the stress test. Patients walk up to the maximum level of pain, which defines the maximum walk distance, but also points out the time of pain onset, thus defining the pain-free walking distance. Alternatively, the six-minute walking test (6MWT) can be used.
The ankle-brachial index (ABI) is an inexpensive, easy to use and interpret and widely used tool for the diagnosis and monitoring of patients with PAD. Resting ABI has 68–84% sensitivity and 84–99% specificity for the diagnosis of PAD. A value of ABI ≤0.9 confirms the diagnosis of PAD, while values >1.4 require are considered “incompressible arteries” and are associated with arterial stiffness in diabetes, renal failure and older age. Both values are associated with an increased CV risk. With an ABI value >1.4, the recommendation is to use the toe-brachial index (TBI), toe pressure (TP) or duplex ultrasound. TBI measures pressure on the thumb, second or third toe using a laser doppler probe or plethysmography. The pathological finding of TBI is ≤0.7. In patients with limb pain during exercise and normal ABI values at rest, it is recommended to measure the ABI after exercise. A positive test is determined by a drop in ankle blood pressure >30 mmHg or a reduction in ABI value >20%. Measurement of transcutaneous oxygen pressure (TcPO2) is important for assessing tissue viability, having in mind that values can be affected by skin thickness, probe temperature, inflammation, and edema. A resting TcPO2 value >30 mmHg is a predictor of wound healing, while a value <10 mmHg is associated with a worse prognosis for wound healing and the risk of amputation.
Duplex ultrasound is the first step in the treatment of arterial disease in which vascular lesions are localised and quantified. The sensitivity is 88%, and the specificity 95% in the assessment of lesions >50%. ABI and duplex ultrasound are also recommended for monitoring PAD after revascularisation.
Considering the increased CV risk, even in asymptomatic PAD patients, timely diagnosis, prevention and control of CV risk factors are important. The recommendation is to perform screening with ABI or TBI in patients over the age of 65 with CV risk factors (class IIa recommendation) or in patients over the age of 65 without CV risk factors (class IIb recommendation). In patients with AAA, screening of the femoropopliteal area with duplex ultrasound is recommended in order to detect a femoropopliteal aneurysm. Screening of asymptomatic patients with carotid artery stenosis in the general population is not recommended. It is recommended to scan for carotid stenosis by duplex ultrasound in patients over the age of 60 with two or more CV risk factors, hypertension and heart disease, treated with hemodialysis, with diagnosed PAD, with known coronary heart disease (before coronary artery bypass grafting), with carotid murmur and after radiation of the carotid area.
Polyvascular disease is defined as the presence of symptomatic atherosclerosis in two or more vascular territories and is common in patients with atherosclerotic disease (Figure 1). There is no evidence that screening for asymptomatic disease in other (additional) vascular territories improves patient outcomes.
Peripheral arterial disease can be asymptomatic or symptomatic and can be associated with limb wounds. Two classifications are used – the Rutherford classification (categories 0–6) and the Fontaine classification (stages I–IV). Patients with asymptomatic PAD do not have typical symptoms, but it is necessary to pay attention to patients with wounds, who have masked symptoms related to gait due to reduced walk distance or reduced pain sensation. Symptomatic PAD (exercise-related) presents with intermittent claudication or chronic wounds without critically reduced limb perfusion, while some patients may present with atypical symptoms. Chronic limb-threatening ischemia (CLTI) is a more severe form of PAD with a poor outcome if limb revascularisation is not performed promptly. In addition to clinical features including ischemic pain at rest, chronic ulcer (duration >2 weeks) or gangrene, hemodynamic parameters including ankle pressure <50 mmHg, TP <30 mmHg or TcPO2 <30 mmHg are also important. In patients with PAD and chronic wounds, the so-called WifI classification serves to assess the risk of amputation, and is scored depending on the type of wound, ABI, AP and TP or TcPO2 values, and the presence of foot infection.
Treatment of peripheral arterial disease
Treatment of PAD is carried out with the aim of preventing major CV events, preventing limb events and improving the quality of life. All patients with detected PAD must be aggressively treated with pharmacological and non-pharmacological measures that are proven to have an impact on patient outcomes, regardless of the initial clinical presentation.
The above includes: smoking cessation, dieting, weight reduction, and pharmacologically mediated optimisation of arterial pressure, cholesterol level, and glycemia values, as well as antithrombotic therapy. In patients with a symptomatic form of PAD, it is necessary, in addition to the above, to carry out structured and guided walking exercises.
Exercise. The mentioned exercises can be performed in hospital settings or at home, at least three times a week, for at least 30 minutes, during 12 weeks. The elements included in the exercises are usually of mild to moderate intensity, with the aim of reducing symptoms and CV risk and increasing the quality of life, walk distance, functional status and the patients’ awareness of their own illness. Depending on the patients’ tolerance, the intensity of the exercises should be gradually increased. Walking is the most accepted form of exercise, but strength exercises, exercises on a cycle-ergometer or a combination of several different exercise regimes are also considered.
Antiplatelet treatment of patients with asymptomatic PAD. There is still no clear evidence that patients with asymptomatic PAD, despite a reduced ankle-brachial index (ABI), have prognostic benefits if they are treated with antiplatelet therapy. The possibility of a beneficial effect of acetylsalicylic acid (ASA, aspirin) cannot be ruled out in certain subgroups of patients (e.g. in patients with diabetes), and patients with manifest atherosclerotic disease in another vascular territory have an indication for antiplatelet treatment. (2)
Antiplatelet treatment of patients with symptomatic PAD. In patients with symptomatic PAD, antiplatelet therapy improves CV prognosis and reduces the risk of CV events and limb events. Clopidogrel can have an advantage over aspirin. The EUCLID trial did not show a greater benefit of ticagrelor over clopidogrel in reducing MACE or major bleeding. The combination of aspirin and rivaroxaban in the so-called vascular dose (2.5 mg twice daily) is more effective than aspirin alone in reducing MACE, MALE, and acute limb ischemia, bearing in mind an increased risk of major bleeding, but no higher incidence of intracerebral or life-threatening bleeding.
Dual antiplatelet therapy (DAPT) is indicated during one to three months after endovascular therapy. The combination of aspirin and rivaroxaban, introduced after revascularisation, reduced the frequency of MALE and MACE without increasing life-threatening bleeding, but with an increase in the incidence of bleeding according to the ISTH classification (International Society on Thrombosis and Haemostasis), especially when used in combination with clopidogrel for more than a month. In patients who have another indication for oral anticoagulant therapy (such as atrial fibrillation or mechanical valves) and PAD, anticoagulant therapy is mandatory, while additional antiplatelet monotherapy after endovascular treatment should last one to three months.
Antihypertensive therapy. The new 2024 ESC Guidelines on arterial hypertension (3) recommend target systolic pressure values of 120–129 mmHg for most adults, if therapy is well tolerated. In case of poor tolerance of the therapy, the goal should be the “lowest reasonably achievable” arterial pressure. Patients with PAD and hypertension have a high CV risk and antihypertensive drugs, such as ACE inhibitors, ARBs, beta-blockers, diuretics and calcium channel blockers are recommended. ACE inhibitors or ARBs should be the first-line treatment to reduce CV events, and combination therapy may be necessary to achieve target arterial pressure values. (4) Antihypertensive treatment can prolong walk distance in PAD patients.
Hypolipemic therapy. Patients with symptomatic PAD are often insufficiently and unsatisfactorily treated when compared to those with coronary artery disease. Lowering LDL cholesterol by more than 50% from baseline and achieving a target LDL-C level <1.4 mmol/L is recommended to reduce mortality, myocardial infarction and stroke, number of amputations, and improve walk distance. Statins are effective in reducing CV events and mortality in PAD patients, even in advanced stages of the disease, and they also reduce the incidence of MALE. Ezetimibe can be combined with statins to improve treatment outcomes in selected PAD patients, especially when target LDL levels have not been achieved. PCSK9 inhibitors, when used in addition to statins, further reduce the risk of MACE and MALE, and improve walk distance. In clinical trials, including those with PAD, inclisiran showed a 26% reduction in the risk of MACE. Bempedoic acid, which inhibits cholesterol biosynthesis, lowers cholesterol levels and can reduce the incidence of MACE in statin-intolerant patients. Although fibrates have not shown significant benefits in reducing CV events in patients with PAD, research suggests that they may have a role in controlling triglyceride levels.
Antidiabetics. Diabetes significantly increases the risk of PAD, and patients with PAD should be screened for diabetes. Diabetes is present in 30% of patients with intermittent claudication and 50–70% of those with critical limb ischemia. Achieving a HbA1c level below 7% is recommended to avoid significant hypoglycemia. Drugs with proven cardiovascular benefits, such as SGLT2 inhibitors and GLP-1 agonists, are recommended for treatment, with the addition of metformin as needed. Research shows that GLP-1RA (LEADER and SUSTAIN-6 trials) and SGLT2 inhibitors (EMPA-REG OUTCOME trial) reduce the risk of CV events in high-risk patients, while empagliflozin shows a reduction in CV risk and overall mortality in patients with type 2 diabetes and PAD. Although metformin and GLP-1RA are associated with a reduction in the risk of MALE and MACE, it is important to consider individualised treatment approaches. SGLT2 inhibitors did not significantly reduce the incidence of stroke, but there is evidence that metformin can reduce aortic growth in patients with AAA. Monitoring of diabetic patients with PAD is essential because of their high risk of CV complications.
Other medications. Verapamil, statins, antiplatelets, and prostanoids can improve the length of the pain-free walk distance in PAD patients, while other drugs, such as cilostazol and naftidrofuryl, enable a significant prolongation of the pain-free walk distance, but without a significant impact on CV outcomes. However, cilostazol can increase the risk of bleeding, which requires caution when combined with other antiplatelet drugs.
Revascularisation. A revascularisation treatment is an option in PAD patients with impaired quality of life due to claudication and shortened pain-free walk distance or with chronic limb-threatening ischemia (CLTI). Revascularisation treatment, except in the case of CLTI, has no significant impact on major CV events and it is advisable to carry it out after three months of optimal medical treatment and controlled exercises, if the goals have not been achieved. In asymptomatic patients, revascularisation methods are not indicated.
Aortoiliac lesions can be effectively treated with endovascular and surgical methods, with the choice depending on lesion features and the risk for the patient. Balloon angioplasty and primary stenting show long-term patency with a low complication rate. However, open surgery shows superior early and medium-term primary patency, while secondary patencies are comparable in both therapeutic methods.
Revascularisation of femoropopliteal lesions should initially include endovascular treatment, even for complex lesions, especially in high-risk surgical patients. Despite the challenges of maintaining long-term patency in the femoropopliteal region, the use of drug-eluting balloons has improved outcomes in complex lesions. Unlike the previous ones, these guidelines state that the length of the lesion is not a decisive criterion for choosing the mode of revascularisation. After initial concerns about paclitaxel-coated materials, an analysis of large national databases did not confirm the earlier suspicion of increased mortality, leading to a revision of the FDA’s position, which now considers the therapy safe and effective. If an autologous vein is available and the patient is at low surgical risk, an open surgical approach should be considered after consultation with an interdisciplinary vascular team. In patients with severe ischemic disease, below-the-knee (BTK) arterial disease can be treated simultaneously during endovascular surgery on femoropopliteal arteries.
Chronic limb-threatening ischemia (CLTI) is defined by long-term hypoperfusion of the lower limbs, causing ischemic pain at rest, non-healing wounds or gangrene. Diagnostic criteria include ankle pressure <50 mmHg, thumb pressure <30 mmHg, or tissue oximetry <30 mmHg. Standard ABI measurements can be unreliable due to non-compressible arteries, so alternative methods of perfusion assessment are recommended. For patients with CLTI, vascular imaging is mandatory to evaluate the possibilities of revascularisation, with additional digital subtraction angiography (DSA) to evaluate the lower leg arteries. Mandatory revascularisation is recommended to restore blood flow and reduce the risk of amputation. Comparisons of endovascular approaches and surgery have shown similar survival and amputation rates, but surgery has long-term benefits. Polyvascular disease requires an individual approach with a multidisciplinary team, while hybrid methods can be considered for combined lesions. In femoropopliteal lesions, it is necessary to preserve possible sites for bypass grafts. For infrapopliteal lesions, endovascular therapy is the first choice, and balloon angioplasty has been shown to be effective. In cases of extensive necrosis, primary amputation may be a better option to avoid complications.
After revascularisation, monitoring is recommended at least once a year, including assessment of the clinical condition, determination of the ABI index and, if necessary, ultrasound examinations. (5,6)
About 20-30% of PAD patients have left ventricular dysfunction, mostly associated with coronary artery disease. PAD and heart failure are independently associated with poor outcomes and the PAD patients with concomitant heart failure have a 30% higher risk of MACE and a 40% higher risk of all-cause mortality. Evaluation of left ventricular function in patients with PAD can be useful for better CV risk stratification and comprehensive management of CV disease. As expected, the presence of PAD in patients with heart failure is also associated with poor outcomes.
The prevalence of atrial fibrillation (AF) in patients with PAD is about 12%. In patients with AF and PAD, the risk of all-cause mortality, CV mortality and MACE is significantly increased. (7) PAD is included in the CHA2DS2-VASc scoring system, which emphasises the prognostic significance of PAD in patients with AF.